Acylpyrroledicarboxylic acids and acylindoledicarboxylic...

Details Acylpyrroledicarboxylic acids and acylindoledicarboxylic... Acylpyrroledicarboxylic acids and acylindoledicarboxylic...

1999-01-29

2001-10-30

Higel, Floyd D. (Department: 1613)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S491000, C548S562000, C514S419000, C514S423000

Reexamination Certificate

active

06310217

ABSTRACT:

The present invention relates to novel acylpyrroledicarboxylic acids and acylindoledicarboxylic acids, and their derivatives, which inhibit the enzyme phospholipase A
2
. These compounds are suitable as pharmaceuticals for preventing and treating disorders caused or partly caused by an increased activity of this enzyme, such as, for example, inflammations, pain, fever, allergies, asthma, psoriasis and endotoxic shock. The invention further relates to methods for synthesizing these compounds and to pharmaceutical compositions comprising these compounds.
It is known that phospholipase A
2
cleaves the ester linkage in position 2 of membrane phospholipids by hydrolysis, producing free fatty acids, mainly arachidonic acid, and lyso-phospholipids.
The liberated arachidonic acid is metabolized by the cyclooxygenase pathway to the prostaglandins and thromboxanes and by the lipoxygenase pathway to the leukotrienes and other hydroxylated fatty acids. The prostaglandins are essentially involved in the production of pain and fever and in inflammatory reactions. Leukotrienes are important mediators in inflammatory processes and in anaphylactic and allergic processes (Forth et al., Allgemeine und Spezielle Pharmakologie and Toxikologie BI Wissenschaftsverlag Mannheim, Vienna, Zurich, 1987).
The lyso-phospholipids formed by phospholipase A
2
have cytotoxic properties. Lyso-phosphatidylserine leads to the release of histamine which is involved in allergic processes (Moreno et al., Agents Actions 1992, 36, 258). Lyso-phosphatidylcholine is moreover metabolized to platelet-activating factor (PAF) which is likewise an important mediator, for example in inflammations.
Since phospholipase A
2
is the key enzyme for formation of said pathophysiologically significant mediators, these mediator effects can be eliminated by inhibiting the enzyme.
Some pyrrole derivatives have already been disclosed as antiinflammatory and analgesic agents. The effect of the substance tolmetin (5-(4-methylbenzoyl)-pyrrol-2-ylacetic acid) which has already been approved as pharmaceutical (U. Ficke et al. Neue Arzeimittel 1993, Wissenschaftliche Verlagsgesellschaft, Stuttgart 1994, pages 20 et seq.) and the benzoylpyrrolealkanoic acids disclosed in German Published Specification 3,415,321 is based on inhibition of cyclooxygenase. The result of inhibition of cyclooxygenase is that more arachidonic acid, which is synthesized in the preceding step in a reaction catalyzed by phospholipase A
2
, is available for lipoxygenase metabolism. This further intensifies certain symptoms of inflammation caused by lipoxygenase-dependent arachidonic acid derivatives. German Published Specification 2,302,669 discloses 1-methyl-5-(3-phenylacryloyl)pyrrol-2-ylformic acid as a compound with an analgesic effect in mice.
In addition, some compounds are known as phospholipase A
2
inhibitors. WO 88-06,885 discloses aminoalkylamides and EP-A-377 539 discloses 4-aryloyl-pyrrol-2-ylformic acids with an inhibitory effect on phospholipase A
2
.
Indole-2-alkanoic acids are disclosed as analgesics with an inhibitory effect on prostaglandins and thromboxanes in U.S. Pat. No. 5,081,145. U.S. Pat. No. 5,132,319 describes 1-(hydroxylaminoalkyl)indole derivatives which inhibit leukotriene biosynthesis. This results in these compounds having an analgesic and antiinflammatory effect. The (azaarylmethoxy)indoles disclosed in EP-A-535 923 likewise inhibit leukotriene biosynthesis.
The fact that certain acylpyrrolealkanoic acids and indole-2-alkanoic acids and their derivatives are able to inhibit phospholipase A
2
is already known from WO 95/13266. Although the acylpyrrolealkanoic acids and indole-2-alkanoic acids disclosed therein are potent phospholipase A
2
inhibitors, there is a need in the specialty for novel compounds having a further improved inhibitory effect and/or less cytotoxicity.
It is therefore the object of the present invention to provide antiinflammatory and analgesic agents which have an improved inhibitory effect and/or less cytotoxicity than compounds known in the prior art. Whereas the antiinflammatory and analgesic effects of nonsteroidal antiinflammatory agents currently available for therapy are based on inhibition of prostaglandin formation resulting from inhibition of the enzyme cyclooxygenase, the claimed substances, like the compounds disclosed in WO 95/13266, are intended to inhibit the enzyme phospholipase A
2
. This results in suppression not only of the biosynthesis of the prostaglandins involved in inflammatory processes and in the pain process, but also of the formation of leukotrienes, of platelet-activating factor and of lyso-phospholipids.
It has now been found, unexpectedly, that pyrrolecarboxylic acid derivatives and indolecarboxylic acid derivatives with certain combinations of substituents have an improved inhibitory effect and less cytotoxicity than the known derivatives and therefore can be utilized better than the latter for preventing and/or treating disorders caused or partly caused by an increased activity of the enzyme phospholipase A
2
, such as, for example, inflammations, allergies, asthma, psoriasis and endotoxic shock.
It is known that there are several different phospholipases A
2
(Connolly and Robinson, Drug News & Perspectives 1993, 6, 584-590). The key enzyme in the biosynthesis of said pathophysiologically significant lipid mediators is so-called cytosolic phospholipase A
2
(cPLA
2
) (Clark et al., J. Lipid Mediators Cell Signalling 1995, 12, 83-117). The compounds according to the invention inhibit in particular this cPLA
2
.
The present invention thus relates to substituted pyrrole compounds and substituted indole compounds of the general formulae I and II:
in which
R
1
is a radical —Y
1
—Ar—Y
2
—Y
3
where Y
1
is a C
1
-C
12
-alkyl, C
2
-C
12
-alkenyl, C
1
-C
12
-alkyloxy or C
2
-C
12
-alkenyloxy radical which can optionally be interrupted by one or more oxygen atoms, Ar is an aryl group which may optionally be substituted by 1 to 3 substituents selected from the group R
6
, R
7
and R
8
, Y
2
is a C
1
-C
12
-alkyl, C
2
-C
12
-alkenyl, C
1
-C
12
-alkyloxy or C
2
-C
12
-alkenyloxy radical which can optionally be interrupted by one or more oxygen atoms, and Y
3
is —COOR
17
, —CONR
17
R
17
, —CONHCOR
19
, —CONHS (O)
2
R
19
, —CONHNHS(O)
2
R
19
, or —Tz where Tz is 1H— or 2H-tetrazol-5-yl;
R
2
is —COOR
17
, —Y
4
—COOR
17
, —CONR
17
R
17
, —Y
4
—CONR
17
R
17
, —CONHCOR
19
, —Y
4
—CONHCOR
19
, —CONHS(O)
2
R
19
, —Y
4
—CONHS (O)
2
R
19
, —CONHNS(O)
2
R
19
, —Y
4
—CONHNHS(O)
2
R
19
, —Tz or —Y
4
—Tz where Y
4
is a C
1
-C
8
-alkyl or C
2
-C
8
-alkenyl group which can optionally be interrupted by an oxygen atom, and Tz is 1H— or 2H-tetrazol-5-yl;
R
3
is —CO—R
9
where R
9
is —Y
5
, -aryl or —Y
5
-aryl, where Y
5
is a C
1
-C
19
-alkyl or C
2
-C
19
-alkenyl or -alkynyl group which can optionally be interrupted by one or more oxygen atoms, and aryl is an aryl group which is optionally substituted by 1 to 3 substituents selected. from the group of R
10
, R
11
and R
12
;
each R
4
radical is, independently of the others, a. hydrogen atom, a halogen atom, —CF
3
, —Y
6
, -aryl or —Y
6
-aryl, where Y
6
is a C
1
-C
8
-alkyl or C
2
-C
8
-alkenyl or -alkynyl group which can optionally be interrupted by one or more oxygen atoms, and aryl is an aryl group which is optionally substituted by 1 to 3 substituents selected from the group of R
13
, R
14
and R
15
, and n is the number 2; and where two Y
6
radicals can, if they are two adjacent alkyl radicals, form together with the carbon atom to which they are bonded a 5-8-membered ring which may optionally be substituted by 1 to 2 C
1
-C
4
-alkyl groups; each R
5
radical is, independently of the others, a hydrogen atom or R
16
, and m is the number 4; R
6
, R
7
, R
8
, R
10
, R
11
, R
12
, R
13
, R
14
, R
15
and R
16
are selected independently of one another from:
(1) C
1
-C
20
-alkyl group which can optionally be interrupted by an oxygen heteroatom;
(2) C
2
-C
20
-alkenyl group which can optionally be interrupted by an oxygen heteroatom;
(3) C
2
-C
20
-a

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